83783-28-2Relevant articles and documents
Structure-based linker exploration: Discovery of 1-ethyl-1H-indole analogs as novel ATX inhibitors
Jia, Fang,Lei, Hongrui,Chen, Yuxiang,Li, Tong,Xing, Lingyun,Cao, Zhi,Zhai, Xin
, (2020)
Aiming to develop novel ATX inhibitors, an indole-3-carboxylic acid lead Indole-1 was identified through high-throughput screening (HTS) efforts. The Indole-1 analogs 1–7 was firstly prepared which exerted mild activity comparable to Indole-1 (740 nM) in ATX enzyme assay. Further structural modification to identify type IV ATX inhibitors was proceeded through derivatization of the indole-3-carboxylic acid group. Resultantly, compounds 8–17 containing acyl hydrazone linker displayed poor activity (over 3.49 μM). Alternatively, replacing the acylhydrazone linker with urea counterpart by the amide bond reversal principle, the acquired compounds 18–22 achieved obvious improvements with submicromolar activities. Furthermore, with the aim to reducing cLogP, the thiazole ring of 18–22 was altered to the benzamide (23–32) with the urea linker unchanged. Remarkably, the benzamide derivative 24 with 4-hydroxy piperidine fragment was identified which exhibited prominent activity with IC50 value of 2.3 nM. Especially, dedicated molecular docking study was throughout the modification process which qualified 24 as optimal entity in accordance with the ATX inhibitory results.
Discovery of Novel Indole-Based Allosteric Highly Potent ATX Inhibitors with Great in Vivo Efficacy in a Mouse Lung Fibrosis Model
Lei, Hongrui,Guo, Ming,Li, Xiaopeng,Jia, Fang,Li, Changtao,Yang, Yu,Cao, Meng,Jiang, Nan,Ma, Enlong,Zhai, Xin
, p. 7326 - 7346 (2020/09/11)
Autotaxin (ATX) is the dominant catalytic enzyme accounting for the lipid mediator lysophosphatidic acid (LPA) through hydrolysis of lysophosphatidylcholine (LPC). There is great interest in developing nonacidic ATX inhibitors with a specific binding mode to serve as potential in vivo effective therapeutic tools. Herein, dating from a high-throughput screening (HTS) product Indole-1 (740 nM), a dedicated optimization campaign was implemented through derivatizing the-COOH group to versatile linkers that well-bridged the indole skeleton and the hydrophobic pocket binding groups. Ultimately, it was established that the coexistence of a carbamate linker and-OH-group-containing amines could generally furnish excellent indole-based ATX inhibitors with even below 1 nM in vitro activities. Two optimal entities were advanced to a bleomycin-induced mice pulmonary fibrosis model, which exerted promising efficacy in alleviating the damaged lung texture caused by bleomycin exposure. The novel carbamate-containing indole-based ATX inhibitors with a concrete binding mode may contribute to the identification of potential therapeutic agents to intervene in fibrotic diseases.
Introducing tetramethylurea as a new methylene precursor: a microwave-assisted RuCl3-catalyzed cross dehydrogenative coupling approach to bis(indolyl)methanes
Deb, Mohit L.,Borpatra, Paran J.,Saikia, Prakash J.,Baruah, Pranjal K.
supporting information, p. 1435 - 1443 (2017/02/15)
Herein we report a microwave assisted Ru(iii)/TBHP-mediated reaction of indoles with tetramethylurea (TMU) synthesizing symmetrical as well as unsymmetrical bis(indolyl)methanes, where TMU acts as a methylenating agent. This is the first report where TMU is used as a methylene source. Moreover, the synthesis of unsymmetrical bis(indolyl)methanes by using a carbon precursor is also reported herein for the first time. Various substituted indoles are used for the reaction. The reaction is high yielding and takes a much shorter time to accomplish compared to the existing methods.
